Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children.

BACKGROUND: The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. PROCEDURE: . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. RESULTS: . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 × 10(-5) and P = 3.0 × 10(-5), respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). CONCLUSIONS: . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options.

Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin.

Statins reduce cardiovascular morbidity and mortality in appropriately selected patients. However, statin-associated myopathy is a significant risk associated with these agents. Recently, variation in the SLCO1B1 gene was reported to predict simvastatin-associated myopathy. The aim of this study was to replicate association of the rs4149056 variant in SLCO1B1 with severe statin-associated myopathy in a cohort of patients using a variety of statin medications and to investigate the association with specific statin types. We identified 25 cases of severe statin-associated myopathy and 84 controls matched for age, gender, statin type and dose. The rs4149056 variant in SLCO1B1 was not significantly associated with myopathy in this group as a whole. However, when subjects were stratified by statin type, the SLCO1B1 rs4149056 genotype was significantly associated with myopathy in patients who received simvastatin, but not in patients who received atorvastatin. Our findings provide further support for a role for SLCO1B1 genotype in simvastatin-associated myopathy, and suggest that this association may be stronger for simvastatin compared with atorvastatin.

Application of principal component analysis to pharmacogenomic studies in Canada.

Ethnicity can confound results in pharmacogenomic studies. Allele frequencies of loci that influence drug metabolism can vary substantially between different ethnicities and underlying ancestral genetic differences can lead to spurious findings in pharmacogenomic association studies. We evaluated the application of principal component analysis (PCA) in a pharmacogenomic study in Canada to detect and correct for genetic ancestry differences using genotype data from 2094 loci in 220 key drug biotransformation genes. Using 89 Coriell worldwide reference samples, we observed a strong correlation between principal component values and geographic origin. We further applied PCA to accurately infer the genetic ancestry in our ethnically diverse Canadian cohort of 524 patients from the GATC study of severe adverse drug reactions. We show that PCA can be successfully applied in pharmacogenomic studies using a limited set of markers to detect underlying differences in genetic ancestry thereby maximizing power and minimizing false-positive findings.

Paleoatmospheric signatures in neogene fossil leaves.

An increase in the atmospheric carbon dioxide (CO(2)) concentration results in a decrease in the number of leaf stomata. This relation is known both from historical observations of vegetation over the past 200 years and from experimental manipulations of microenvironments. Evidence from stomatal frequencies of fossil Quercus petraea leaves indicates that this relation can be applied as a bioindicator for changes in paleoatmospheric CO(2) concentrations during the last 10 million years. The data suggest that late Neogene CO(2) concentrations fluctuated between about 280 and 370 parts per million by volume.

The influence of genetic variation on late toxicities in childhood cancer survivors: A review.

INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.

Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.

The pharmacokinetics of a novel antipsychotic agent, risperidone, and the prolactin response were studied in 12 dextromethorphan-phenotyped healthy men after administration of 1 mg risperidone intravenously, intramuscularly, and orally. The formation of the equipotent major metabolite, 9-hydroxyrisperidone, exhibited CYP2D6-related polymorphism. The plasma area under the concentration-time curve from time zero to infinity ratio of 9-hydroxyrisperidone to risperidone averaged 3 (intravenous and intramuscular) and 6 (oral administration) in the extensive metabolizers and 0.2 in the poor metabolizers. Risperidone half-life was about 3 hours in extensive metabolizers and 22 hours in poor metabolizers. Risperidone absolute oral bioavailability was 66%. The pharmacokinetics of the active moiety (risperidone plus 9-hydroxyrisperidone) varied little among subjects (mean terminal half-life, 20 +/- 2 1/2 hours; absolute oral and intramuscular bioavailability, 100%). The prolactin response correlated best with the plasma active moiety, which showed little hysteresis. It is concluded that risperidone metabolic polymorphism on increased plasma prolactin is minimal and that the active moiety is clinically relevant.

Validity and purpose of in-training examination in obstetrics and gynecology, 1979-1982.

Since its creation in 1967, the Council on Resident Education in Obstetrics and Gynecology (CREOG) in-training examination has become an integral part of obstetric and gynecology resident training programs in the United States and Canada. Refinements over the past 12 years have made the examination more useful in fulfilling its intended purpose: to assist program directors in evaluating residents' cognitive knowledge as well as the effectiveness of individual training programs. Based on the educational objectives as defined by CREOG, the results of the examination demonstrate its validity as an educational exercise.

Information management needs of the obstetrician-gynecologist--a survey.

A random sample survey of members of The American College of Obstetricians and Gynecologists (ACOG) was conducted to ascertain the extent to which computer technology was being used by the members, and what further computer services and applications were needed. Computers were used by 38% of the members, with an additional 13% planning on getting a computer within the year. An average of 48% of the members had no plans for computerization, although this number was lower (29%) for physicians 36-45 years of age. There was no significant variation of use by physician sex or type of practice (office- versus non-office-based). Word processing and financial management were the most frequently used computer applications; clinical patient care tasks were used much less frequently and were presumably less available, because software for these tasks was also highly desirable. The most desired information services were uniform coding and terminology, high-risk patient management, electronic access to full-text obstetric and gynecologic data bases, and online clinical management protocols. Prescription writing, patient recall by drug, and drug inventory computer applications were among the least requested. Several educational, project development, communication, and member service strategies have been formulated to integrate medical information management activities for ACOG members.

Guidelines for the elective induction of labor with oral Prostaglandin E2.

Fifty multiparous patients at 37 weeks or more of gestation with a vertex presentation and a Bishop score of 7 or more had labor induced with oral Prostaglandin E2 tablets. All responded and delivered vaginally. The induction to delivery time averaged 4 hours and 44 minutes. The average number of tablets required was 3.64. Four women experienced nausea and an additional 4 women had some vomiting. Two patients showed hypertonus and 11 had frequent contractions. Many progressed rapidly after they began active labor. There was no evidence of fetal distress. Guidelines are suggested for the use of oral Prostaglandin E2 tablets to adequately control the labor process and prevent hypercontractility.

Opinions and approaches to continuing education among obstetrician/gynecologists.

This national survey of Fellows of The American College of Obstetricians and Gynecologists found that obstetrician/gynecologists are actively involved in continuing medical education activities and appear satisfied with the resources available, yet desire additional opportunities for lifelong learning. Traditional resources (eg, journals, seminars) are used much more extensively than newer, electronic resources (eg, video cassettes, cable television), probably as a result of unfamiliarity with these latter methods and limited access to them. However, the majority of Fellows want increased exposure to these newer educational programs. Relevance of content, caliber of faculty, and potential for professional growth were important factors in choosing continuing medical education programs. Strong interest was expressed in individualized learning programs designed in collaboration with university faculty. These findings are of value in producing future educational programs for practitioners in obstetrics and gynecology.

Assessment of the resident in-training examination in obstetrics and gynecology.

An integral component for the evaluation of resident's cognitive knowledge is the examination developed under the auspices of the Council on Resident Education in Obstetrics and Gynecology (CREOG). We sought to assess the usefulness of this annual examination from the perspective of both residents and residency program directors. We were particularly interested in comparing the contemporary use of this examination with the original intent of CREOG when the examination was developed in 1968. In addition, we were interested in determining the role of the examination in modifying educational programs. A questionnaire was mailed to all program directors before the 1994 examination and given to all house staff when the examination was administered. The response rate was 55 and 82%, respectively. Overall, the majority of residents (60%) and program directors (58%) found the examination to be an accurate assessment of cognitive knowledge; feedback on examination results varied widely, and residents used a variety of tools to prepare for the examination.

Genetic markers of cisplatin-induced hearing loss in children.

This journal recently published a Commentary by Ratain and colleagues at the University of Chicago that criticizes our work on cisplatin-induced hearing loss in children. It is unfortunate that neither the authors nor the editors of Clinical Pharmacology & Therapeutics corresponded with us to provide an earlier opportunity to address these questions. Here we correct the authors' inaccuracies and provide additional analyses that further strengthen our published findings.

Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children.

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children.

Zoidogamy in fossil gymnosperms: The centenary of a concept, with special reference to prepollen of late Paleozoic conifers.

This year is the centenary of the surprising discovery in 1896 of zoidogamy in extant cycadophytes and Ginkgo. But by coincidence, also in the same year, the concept of prepollen was introduced. The morphology of prepollen was considered justification for the probable production of motile antherozoids in extinct gymnosperms. In this paper, the history of the prepollen concept is briefly outlined. It is emphasized that, in addition to well-known examples in pteridosperms and cordaitaleans, a prepollen condition also occurred among late Paleozoic conifers.